The effects of nicotine on human fetal development

Mazurek J.M., England L.J.

Employers play a vital role in promoting and supporting tobacco use cessation among tobacco-using workers. Cigarette smoking during pregnancy is a preventable cause of complications in pregnancy and adverse infant health outcomes.To estimate cigarette smoking prevalence and attempts to quit among working women of reproductive age in different industries and occupations using a nationally representative survey.The 2009-2013 National Health Interview Survey data for women of reproductive age (18-49 years) who were working in the week prior to the interview (n = 30855) were analyzed. Data were adjusted for nonresponse and weighted to produce nationally representative estimates.During 2009-2013, among working women of reproductive age, an estimated 17.3% (95% confidence interval [CI]: 16.7-17.8) and 12.9% (95% CI: 12.4-13.4) were current and former cigarette smokers, respectively. Of women who smoke daily, 44.5% (95% CI: 42.5-46.5) had made a quit attempt for more than 1 day in the year before the interview. Cigarette smoking prevalence was highest among women working in the construction industry (29.2%; 95% CI: 22.8-35.7) and in construction and extraction occupations (34.6%; 95% CI: 23.4-45.9). Among working women who were pregnant at the time of the interview, 6.8% (95% CI: 4.4-9.2) and 20.4% (95% CI: 16.9-24.0) were current and former cigarette smokers, respectively.Cigarette smoking prevalence varies by industry and occupation. Intensifying tobacco control efforts in high prevalence industries and occupations could result in higher cessation rates and improvements in health among women of reproductive age.This study identified discrepancies in cigarette smoking among women of reproductive age across industries and occupations. In the absence of smoke-free local and state laws, employer-established smoke-free policies and workplace cessation programs are important for achieving reduction of tobacco use among women and for protecting other workers' health. Results in this report may assist in developing educational campaigns targeting women in industries and occupations with high prevalence of cigarette smoking and low percentage of ever-smokers who had quit.

Kahr M.K., Padgett S., Shope C.D., Griffin E.N., Xie S.S., Gonzalez P.J., Levison J., Mastrobattista J., Abramovici A.R., Northrup T.F., Stotts A.L., Aagaard K.M., Suter M.A.

Studies reveal that electronic cigarette (e-cigarette) and hookah use are increasing among adolescents and young adults. However, the long-term health effects are unknown, especially with regards to pregnancy. Because of the increased use in women of reproductive age, and the unknown long-term health risks, our primary objectives were to determine the perceived risks of e-cigarette and hookah use in pregnancy, and learn common colloquial terms associated with e-cigarettes. Furthermore, we sought to determine if there is a stigma associated with e-cigarette use in pregnancy. Eleven focus groups including 87 participants were conducted immediately following regularly scheduled CenteringPregnancy® prenatal care with women at three different clinics in the greater Houston area. A minimum of two facilitators led the groups, using ten lead-in prompts, with Spanish translation as necessary. Facilitators took notes which were compared immediately following each group discussion and each group was audio recorded and transcribed. Three facilitators utilized NVivo 9.0 software to organize the transcribed data into nodes to identify major themes. To increase rigor, transcripts were further analyzed by two obstetricians who were instructed to find the major themes. Analyses revealed contradicting themes concerning e-cigarette use. In general, e-cigarettes were perceived as safer alternatives to regular tobacco cigarettes, especially if used as smoking cessation devices. A major theme is that use in pregnancy is harmful to the fetus. However, it was perceived that use for smoking cessation in pregnancy may have fewer side effects. We found that a common term for e-cigarettes is “Blu.” In our discussion of hookah use, participants perceived use as popular among teenagers and that use in pregnancy is dangerous for the fetus. Although a strong theme emerged against hookah use, we found contradicting themes in our discussions on e-cigarette use in pregnancy. It is possible that e-cigarette use will not carry the same stigma as regular cigarette smoking in pregnancy. In addition, the impression of e-cigarettes as a healthier alternative to smoking may influence use in pregnancy. Clinicians need to be prepared for questions of e-cigarette safety and efficacy as smoking cessation devices from their pregnant patients who smoke, and women who smoke and are planning to become pregnant.

Mark K.S., Farquhar B., Chisolm M.S., Coleman-Cowger V.H., Terplan M.

Electronic cigarettes (e-cigarettes) are a relatively recent phenomenon, serving dual roles as an alternative vehicle for nicotine delivery and a smoking-cessation tool. The purpose of this study was to determine pregnant women's knowledge, attitudes, and practice regarding electronic cigarettes.A voluntary, anonymous survey was distributed to a convenience sample of pregnant women presenting to a university-based outpatient clinic. After survey completion, participants received information about smoking cessation and e-cigarettes. Data were examined using χ² and Fisher exact tests and analysis of variance. Stata was used for the analysis.Of the 326 surveys distributed, 316 were completed (97%). Of the 316 participants, 42 (13%) reported having ever used e-cigarettes. Only 2 (0.6%) reported current daily use. Ever users were slightly older (27.3 years vs 25.4 years; P = 0.007) and more likely to be current smokers (43% vs. 14%; P < 0.001) compared with women who had never used electronic cigarettes. Knowledge of the harms of smoking was similar between the 2 groups. Overall, 57% of all respondents believed that e-cigarettes contain nicotine, 61% that e-cigarettes can be addictive, and 43% that e-cigarettes are less harmful to a fetus than traditional cigarettes. Among ever users, the most common reasons given for the use of e-cigarettes were the perception of less harm than traditional cigarettes (74%) and help with smoking cessation (72%).Misconceptions about e-cigarettes are common among pregnant women, potentially motivating use that may pose risks to both maternal and child health. Screening and education regarding e-cigarettes should be included in prenatal care. Future research in this area is necessary, including research examining pregnancy outcomes among women who use e-cigarettes.

Daseking M., Petermann F., Tischler T., Waldmann H.-.

Introduction: Maternal nicotine use during pregnancy has a negative impact on the child. Numerous studies have demonstrated an association between smoking during pregnancy and psychological deficits. This study looks at deficits in executive functioning in preschool-aged children. Methods: The executive functioning of preschool children was assessed by asking parents to complete the parental form of the Behavior Rating Inventory of Executive Functions - Preschool Version (BRIEF-P, German version). The results for preschool children whose mothers had smoked during pregnancy (n = 71) were compared with those of a control group. In a subsample, parental assessments of children of smokers (n = 42) and non-smokers (n = 27) were complemented by the teacher form of the BRIEF-P (German version), which allowed inter-rater agreement (parents vs. preschool teachers) to be assessed. Results: An increased incidence of executive function deficits was noted in the children of smokers, based on parental assessment. Clinically relevant deficits were particularly evident with regard to inhibition, with inhibitory deficits in children of smokers found to be almost four times higher than in the control group (p = 0.006). Inhibitory deficits were reported both by parents and by preschool teachers. Discussion: The increased percentage of executive function deficits described here, particularly the increased inhibitory deficits, confirms the current state of research on smoking during pregnancy. Poor inhibition or impulse control is a key symptom of ADHD.Einleitung: Der Nikotinkonsum der Mutter während der Schwangerschaft hat verschiedene negative Folgen für ein Kind. Eine Vielzahl von Studien zeigt dabei auch einen Zusammenhang mit psychischen Verhaltensauffälligkeiten auf. In der vorliegenden Studie soll der Fokus auf Störungen in den exekutiven Funktionen im Kindergartenalter gelegt werden. Methoden: Es wurden die Eltern- und Erziehereinschätzungen zu exekutiven Funktionen im Verhaltensinventar zur Beurteilung exekutiver Funktionen für das Kindergartenalter (BRIEF-P) von 71 Kindergartenkindern, deren Mütter während der Schwangerschaft geraucht haben, mit einer Kontrollgruppe verglichen. Für einen Teil der Kinder von Raucherinnen (n = 42) und von Nichtraucherinnen (n = 27) konnten darüber hinaus die Erzieherinneneinschätzungen im BRIEF-P berücksichtigt werden. Ergebnisse: Im Elternurteil ergab sich für Kinder von Raucherinnen ein gehäuftes Auftreten von Auffälligkeiten in den exekutiven Funktionen. Insbesondere im Bereich der Inhibition zeigten sich fast 4-mal häufiger klinisch relevante Defizite als für die Kinder der Kontrollgruppe (p = 0,006). Die Auffälligkeiten in der Inhibition zeigen sich sowohl im Eltern- als auch im Erzieherurteil. Diskussion: Die hier beschriebene erhöhte Rate an Defiziten in den exekutiven Funktionen, insbesondere im Bereich der Inhibition, bestätigt den Forschungsstand zum Nikotinkonsum während der Schwangerschaft. Mangelnde Inhibition bzw. Impulskontrolle stellt ein Kernsymptom der ADHS dar.

Suter M.A., Mastrobattista J., Sachs M., Aagaard K.

A. Longo C., A. Fried P., Cameron I., M. Smith A.

Using functional magnetic resonance imaging (fMRI), the long-term effects of prenatal nicotine exposure on verbal working memory were investigated in young adults. Participants were members of the Ottawa Prenatal Prospective Study, a longitudinal study that collected a unique body of information on participants from infancy to young adulthood. This allowed for the measurement of an unprecedented number of potentially confounding drug exposure variables including: prenatal marijuana and alcohol exposure and current marijuana, nicotine and alcohol use.Twelve young adults with prenatal nicotine exposure and 13 non-exposed controls performed a 2-Back working memory task while fMRI blood oxygen level-dependent responses were examined. Despite similar task performance, participants with more prenatal nicotine exposure demonstrated significantly greater activity in several regions of the brain that typically subserve verbal working memory including the middle frontal gyrus, precentral gyrus, the inferior parietal lobe and the cingulate gyrus.These results suggest that prenatal nicotine exposure contributes to altered neural functioning during verbal working memory that continues into adulthood. Working memory is critical for a wide range of cognitive skills such as language comprehension, learning and reasoning.Thus, these findings highlight the need for continued educational programs and public awareness campaigns to reduce tobacco use among pregnant women.

Dutra L.M., Glantz S.A.

Ekblad M., Korkeila J., Lehtonen L.

Environmental factors such as maternal smoking can significantly modulate genetically programmed brain development during foetal life. This review looks at how prenatal smoking exposure modulates brain development, including new evidence on the effects of smoking on foetal brain development and function.Smoking during pregnancy exposes the foetus to thousands of health-threatening chemicals, restricting foetal body and head growth. Alterations in brain structure and function have been seen in children exposed to prenatal smoking.

Harrod C.S., Reynolds R.M., Chasan-Taber L., Fingerlin T.E., Glueck D.H., Brinton J.T., Dabelea D.

To examine the dose-dependent and time-specific relationships of prenatal smoking with neonatal body mass, fat mass (FM), fat-free mass (FFM), and FM-to-FFM ratio, as measured by air-displacement plethysmography (PEA POD system).We analyzed 916 mother-neonate pairs participating in the longitudinal prebirth cohort Healthy Start study. Maternal prenatal smoking information was collected in early, middle, and late pregnancy by self-report. Neonatal body composition was measured with the PEA POD system after delivery. Multiple general linear regression models were adjusted for maternal and neonatal characteristics.Each additional pack of cigarettes smoked during pregnancy was associated with significant decreases in neonatal body mass (adjusted mean difference, -2.8 g; 95% CI, -3.9 to -1.8 g; P < .001), FM (-0.7 g; 95% CI, -1.1 to -0.3 g; P < .001), and FFM (-2.1 g; 95% CI, -2.9 to -1.3 g; P < .001). Neonates exposed to prenatal smoking throughout pregnancy had significantly lower body mass (P < .001), FM (P < .001), and FFM (P < .001) compared with those not exposed to smoking. However, neonates of mothers who smoked only before late pregnancy had no significant differences in body mass (P = .47), FM (P = .43), or FFM (P = .59) compared with unexposed offspring.Exposure to prenatal smoking leads to systematic growth restriction. Smoking cessation before late pregnancy may reduce the consequences of exposure to prenatal smoking on body composition. Follow-up of this cohort is needed to determine the influence of catch-up growth on early-life body composition and the risk of childhood obesity.

Baeza-Loya S., Viswanath H., Carter A., Molfese D.L., Velasquez K.M., Baldwin P.R., Thompson-Lake D.G., Sharp C., Fowler J.C., De La Garza R., Salas R.

Tiesler C.M., Heinrich J.

In utero exposure to tobacco smoke has been related to numerous adverse health effects in new-borns, infants, children, adolescents and adults. The aim of this review was to summarise findings on prenatal nicotine exposure and its relationship with behavioural problems in the offspring. The majority of studies, and especially several recent epidemiological studies, observed a higher likelihood for attention-deficit/hyperactivity disorder (ADHD) or ADHD symptoms in exposed subjects. However, both human and animal studies have failed to provide clear evidence on causality. Existing literature on studies investigating the association between prenatal nicotine exposure and conduct or externalising problems in the offspring suggests a causal effect. The establishment of a final conclusion concerning the relationship between prenatal nicotine exposure and internalising problems in the offspring is complicated by insufficient data and mixed results in epidemiological studies. Prenatal nicotine exposure has been associated with altered brain structure and function in human offspring, and a proposed biological mechanism is related to nicotine’s adverse influence on neurotransmitter systems during brain development. In conclusion, establishing a statement on the causality of the relationship between prenatal nicotine exposure and behavioural problems in children remains a challenging task. Nevertheless, considering the results of an increasing number of studies which link prenatal exposure to nicotine to externalising problems applying different methodologies to account for confounding and in view of other adverse health effects known to be caused by this exposure, parents should consider smoking cessation.

Zhu J.L., Olsen J., Liew Z., Li J., Niclasen J., Obel C.

BACKGROUND: Prenatal maternal smoking has been associated with attention-deficit/hyperactivity disorder (ADHD) in children, but the causal nature of this association is still under scrutiny. We examined the association with maternal smoking and nicotine replacement use during pregnancy, using association with paternal smoking as a marker of potential genetic or social confounding. METHODS: We included 84 803 singletons who participated in the Danish National Birth Cohort. Information on parental smoking was reported by the mothers during pregnancy. Children with ADHD were identified from the Danish Psychiatric Central Register, the Danish National Patient Register, and the Register of Medicinal Product Statistics by the International Classification of Diseases, 10th Revision diagnosis or medication. We also used hyperactivity/inattention score of the parent-reported Strengths and Difficulties Questionnaire, included in the 7-year follow-up of the National Birth Cohort. RESULTS: Maternal and paternal smoking during pregnancy were associated with an elevated risk of ADHD defined by hospital diagnosis, medication, and hyperactivity/inattention score, but the association was stronger for maternal smoking than for paternal smoking. Compared with children born to nonsmoking mothers and smoking fathers, children born of smoking mothers and nonsmoking fathers had a higher risk of ADHD (adjusted hazard ratio = 1.26; 95% confidence interval, 1.03 to 1.53). We also saw a higher risk of ADHD in children of mothers who used nicotine replacement during pregnancy. CONCLUSIONS: Our findings indicate that the association between prenatal maternal smoking and ADHD may overestimate a causal link, but nicotine exposure or related factors may still play a causal role.

Holz N.E., Boecker R., Baumeister S., Hohm E., Zohsel K., Buchmann A.F., Blomeyer D., Jennen-Steinmetz C., Hohmann S., Wolf I., Plichta M.M., Meyer-Lindenberg A., Banaschewski T., Brandeis D., Laucht M.

There is accumulating evidence relating maternal smoking during pregnancy to attention-deficit/hyperactivity disorder (ADHD) without elucidating specific mechanisms. Research investigating the neurobiological underpinnings of this disorder has implicated deficits during response inhibition. Attempts to uncover the effect of prenatal exposure to nicotine on inhibitory control may thus be of high clinical importance.To clarify the influence of maternal smoking during pregnancy (hereafter referred to as prenatal smoking) on the neural circuitry of response inhibition and its association with related behavioral phenotypes such as ADHD and novelty seeking in the mother's offspring.Functional magnetic resonance imaging was performed for the offspring at 25 years of age during a modified Eriksen flanker/NoGo task, and voxel-based morphometry was performed to study brain volume differences of the offspring. Prenatal smoking (1-5 cigarettes per day [14 mothers] or >5 cigarettes per day [24 mothers]) and lifetime ADHD symptoms were determined using standardized parent interviews at the offspring's age of 3 months and over a period of 13 years (from 2 to 15 years of age), respectively. Novelty seeking was assessed at 19 years of age. Analyses were adjusted for sex, parental postnatal smoking, psychosocial and obstetric adversity, maternal prenatal stress, and lifetime substance abuse. A total of 178 young adults (73 males) without current psychopathology from a community sample followed since birth (Mannheim, Germany) participated in the study.Functional magnetic resonance imaging response, morphometric data, lifetime ADHD symptoms, and novelty seeking.Participants prenatally exposed to nicotine exhibited a weaker response in the anterior cingulate cortex (t168 = 4.46; peak Montreal Neurological Institute [MNI] coordinates x = -2, y = 20, z = 30; familywise error [FWE]-corrected P = .003), the right inferior frontal gyrus (t168 = 3.65; peak MNI coordinates x = 44, y = 38, z = 12; FWE-corrected P = .04), the left inferior frontal gyrus (t168 = 4.09; peak MNI coordinates x = -38, y = 36, z = 8; FWE-corrected P = .009), and the supramarginal gyrus (t168 = 5.03; peak MNI coordinates x = 64, y = -28, z = 22; FWE-corrected P = .02) during the processing of the NoGo compared to neutral stimuli, while presenting a decreased volume in the right inferior frontal gyrus. These findings were obtained irrespective of the adjustment of confounders, ADHD symptoms, and novelty seeking. There was an inverse relationship between inferior frontal gyrus activity and ADHD symptoms and between anterior cingulate cortex activity and novelty seeking.These findings point to a functional involvement of prenatal exposure to tobacco smoke in neural alterations similar to ADHD, which underlines the importance of smoking prevention treatments.

Fitzpatrick C., Barnett T.A., Pagani L.S.

In utero exposure to cigarette smoke has been shown to have an adverse effect on healthy brain development in childhood. In the present study, we examine whether fetal exposure to mild and heavy smoking is associated with lower levels of impulsivity and cognitive control at age 10. Using a sample of 2120 children from the Québec Longitudinal Study of Child Development, we examine the association between gestational cigarette smoke exposure and fourth grade teacher reports of impulsivity and classroom engagement which represent behavioral indicators of executive functions. When compared to children of non-smokers, children of mothers who reported smoking heavily during pregnancy (10 or more cigarettes per day) were rated by their fourth grade teachers as displaying higher levels of impulsive behavior, scoring.112 standard deviation units higher than children of non-smokers. Children of mothers who smoked heavily were also less engaged in the classroom, scoring.057 standard deviation units lower than children of women who did not smoke. These analyses were adjusted for many potentially confounding child and family variables. Exposure to perinatal nicotine may compromise subsequent brain development. In particular, fetal nicotine may be associated with impairment in areas recruited for the effortful control of behavior in later childhood, a time when task-orientation and industriousness are imperative for academic success.

Boucher O., Jacobson J.L., Burden M.J., Dewailly É., Jacobson S.W., Muckle G.

Prenatal cigarette smoke exposure (PCSE) has been linked to problems in behavioral inhibition and attention deficit hyperactivity disorder in children in several epidemiological studies. We used event-related potentials (ERPs) to examine the effects of PCSE on neural correlates of inhibitory control of behavior. In a prospective longitudinal study on child development in the Canadian Arctic, we assessed 186 Inuit children (mean age=11.3years) on a visual Go/No-go response inhibition paradigm. PCSE was assessed through maternal recall. Potential confounders were documented from a maternal interview, and exposure to neurotoxic environmental contaminants was assessed from umbilical cord and child blood samples. PCSE was not related to behavioral performance on this simple response inhibition task. Nevertheless, this exposure was associated with smaller amplitudes of the N2 and P3 components elicited by No-go stimuli, suggesting an impairment in the neural processes underlying response inhibition. Amplitude of the No-go P3 component was also inversely associated with behavioral measures of externalizing problems and hyperactivity/impulsivity in the classroom. This study is the first to report neurophysiological evidence of impaired response inhibition in school-aged children exposed to tobacco smoke in utero. Effects were found on ERP components associated with conflict processing and inhibition of a prepotent response, indicating neurophysiological deficits that may play a critical role in the attention and behavior problems observed in children with PCSE.

Kabéle M., Lyytinen G., Bosson J.A., Hedman L., Antoniewicz L., Lundbäck M., Mobarrez F.

Gupta A., Gawde N., Kumar K.A., Sivakami M., Parasuraman S.

Elseifi O.S., Younis F.E., Mirza I.M., Alhewiti A., Abd-Elhady N.M., Mortada E.M.

Background: Smoking during pregnancy is a significant issue because of its impact on maternal and fetal health. This study aimed to ascertain the effects of smoking cessation programs on the smoking abstinence rate and pregnancy outcomes. Methods: A meta-analysis of twenty-one RCTs was carried out in accordance with PRISMA standards. The meta-analysis comprised 8149 pregnant smokers. With RevMan (version 5.4), the pooled effect of RR for different smoking cessation interventions was determined. Using the GRADE approach, the certainty was evaluated. I2 statistics and sensitivity analysis were utilized to measure heterogeneity. Egger’s test and funnel plot analysis were used to assess publication bias. Results: The pregnant women who received cognitive-behavioral counseling and financial incentives recognized a significant rise in their smoking abstinence rate (RR: 1.14, 95% CI: 1.02–1.28, p = 0.03 and RR: 2.37, 95% CI: 1.92–2.93, p < 0.001), but there was no significant difference observed among other behavioral approaches or pharmaceutical therapy. Fetuses born to women in the intervention group had significantly larger birth weights (MD = 94.73, 95% CI = (41.18–58.27), p < 0.001. Conclusions: Pregnant women respond well to cognitive-behavioral counseling and financial incentives for quitting smoking, which improve pregnancy outcomes like birth weight.

Caron K.M., Beeson A.L., Marbrey M.W.

Noël A., Poindexter M.E., Bayat Y., Alizani G.

Hua Y., Habicher J., Carl M., Manuel R., Boije H.

ABSTRACTAcetylcholine (ACh), a vital neurotransmitter for both the peripheral (PNS) and central nervous systems (CNS), signals through nicotinic ACh receptors (nAChRs) and muscarinic ACh receptors (mAChR). Here, we explore the expression patterns of three nAChR subunits, chrna3, chrnb4, and chrna5, which are located in an evolutionary conserved cluster. This close genomic positioning, in a range of vertebrates, may indicate co‐functionality and/or co‐expression. Through novel transgenic zebrafish lines, we observe widespread expression within both the PNS and CNS. In the PNS, we observed expression of chrna3tdTomato, chrnb4eGFP, and chrna5tdTomato in the intestinal enteric nervous system; chrna5tdTomato and chrnb4eGFP in sensory ganglia of the lateral line; and chrnb4eGFP in the ear. In the CNS, the expression of chrnb4eGFP and chrna5tdTomato was found in the retina, all three expressed in diverse regions of the brain, where a portion of chrna3tdTomato and chrnb4eGFP cells were found to be inhibitory efferent neurons projecting to the lateral line. Within the spinal cord, we identify distinct populations of chrna3tdTomato‐, chrnb4eGFP‐, and chrna5tdTomato‐expressing neurons within the locomotor network, including dmrt3a‐expressing interneurons and mnx1‐expressing motor neurons. Notably, three to four primary motor neurons per hemisegment were labeled by both chrna3tdTomato and chrnb4eGFP. Interestingly, we identified an sl‐type secondary motor neuron per hemisegement that strongly expressed chrna5tdTomato and co‐expressed chrnb4eGFP. These transgenic lines provide insights into the potential roles of nAChRs within the locomotor network and open avenues for exploring their role in nicotine exposure and addiction in a range of tissues throughout the nervous system.

Kopa-Stojak P.N., Pawliczak R.

Yu W., Chen Z., Li Y., Jiang S., Zhang L., Shao X.M., Xiao D.

In utero cigarette smoking/nicotine exposure during pregnancy significantly affects fetal development and increases the risk of cardiovascular disease late in life. However, the underlying molecular mechanisms remain largely unknown. We tested the hypothesis that fetal nicotine aerosol exposure reprograms ischemia-sensitive gene expressions, resulting in increased heart susceptibility to ischemic injury and cardiac dysfunction in adulthood.

Dabdoub S.M., Greenlee A., Abboud G., Brengartner L., Zuiker E., Gorr M.W., Wold L.E., Kumar P.S., Cray J.

AbstractThe use of traditional nicotine delivery products such as tobacco has long been linked to detrimental health effects. However, little work to date has focused on the emerging market of aerosolized nicotine delivery known as electronic nicotine delivery systems (ENDS) or electronic cigarettes, and their potential for new effects on human health. Challenges studying these devices include heterogeneity in the formulation of the common components of most available ENDS, including nicotine and a carrier (commonly composed of propylene glycol and vegetable glycerin, or PG/VG). In the present study, we report on experiments interrogating the effects of major identified components in e‐cigarettes. Specifically, the potential concomitant effects of nicotine and common carrier ingredients in commercial “vape” products are explored in vitro to inform the potential health effects on the craniofacial skeleton through novel vectors as compared to traditional tobacco products. MC3T3‐E1 murine pre‐osteoblast cells were cultured in vitro with clinically relevant liquid concentrations of nicotine, propylene glycol (PG), vegetable glycerin (VG), Nicotine+PG/VG, and the vape liquid of a commercial product (Juul). Cells were treated acutely for 24 h and RNA‐Seq was utilized to determine segregating alteration in mRNA signaling. Influential gene targets identified with sparse partial least squares discriminant analysis (sPLS‐DA) implemented in mixOmics were assessed using the PANTHER Classification system for molecular functions, biological processes, cellular components, and pathways of effect. Additional endpoint functional analyses were used to confirm cell cycle changes. The initial excitatory concentration (EC50) studied defined a target concentration of carrier PG/VG liquid that altered the cell cycle of the calvarial cells. Initial sPLS‐DA analysis demonstrated the segregation of nicotine and non‐nicotine exposures utilized in our in vitro modeling. Pathway analysis suggests a strong influence of nicotine exposures on cellular processes including metabolic processes and response to stimuli including autophagic flux. Further interrogation of the individual treatment conditions demonstrated segregation by treatment modality (Control, Nicotine, Carrier (PG+VG), Nicotine+PG/VG) along three dimensions best characterized by: latent variable 1 (PLSDA‐1) showing strong segregation based on nicotine influence on cellular processes associated with cellular adhesion to collagen, osteoblast differentiation, and calcium binding and metabolism; latent variable 2 (PLSDA‐2) showing strong segregation of influence based on PG+VG and Control influence on cell migration, survival, and cycle regulation; and latent variable 3 (PLSDA‐3) showing strong segregation based on Nicotine and Control exposure influence on cell activity and growth and developmental processes. Further, gene co‐expression network analysis implicates targets of the major pathway genes associated with bone growth and development, particularly craniofacial (FGF, Notch, TGFβ, WNT) and analysis of active subnetwork pathways found these additionally overrepresented in the Juul exposure relative to Nicotine+PG/VG. Finally, experimentation confirmed alterations in cell count, and increased evidence of cell stress (markers of autophagy), but no alteration in apoptosis. These data suggest concomitant treatment with Nicotine+PG/VG drives alterations in pre‐osteoblast cell cycle signaling, specifically transcriptomic targets related to cell cycle and potentially cell stress. Although we suspected cell stress and well as cytotoxic effects of Nicotine+PG/VG, no great influence on apoptotic factors was observed. Further RNA‐Seq analysis allowed for the direct interrogation of molecular targets of major pathways involved in bone and craniofacial development, each demonstrating segregation (altered signaling) due to e‐cigarette‐type exposure. These data have implications directed toward ENDS formulation as synergistic effects of Nicotine+PG/VG are evidenced here. Thus, future research will continue to interrogate how varied formulation of Nicotine+PG/VG affects overall cell functions in multiple vital systems.

dos Santos J.F., Brito I.R., de Melo I.S., Oliveira K.B., de Souza F.M., Gitai D.L., Duzzioni M., Bueno N.B., de Araujo L.A., Shetty A.K., de Castro O.W.

Abuse-related drug usage is a public health issue. Drosophila melanogaster has been used as an animal model to study the biological effects of these psychoactive substances in preclinical studies. Our objective in this review is to evaluate the adverse effects produced by cocaine, nicotine, and marijuana during the development of D. melanogaster. We searched experimental studies in which D. melanogaster was exposed to these three psychoactive drugs in seven online databases up to January 2023. Two reviewers independently extracted the data. Fifty-one studies met eligibility criteria and were included in the data extraction: nicotine (n = 26), cocaine (n = 20), and marijuana (n = 5). Fifteen studies were eligible for meta-analysis. Low doses (~0.6 mM) of nicotine increased locomotor activity in fruit flies, while high doses (≥3 mM) led to a decrease. Similarly, exposure to cocaine increased locomotor activity, resulting in decreased climbing response in D. melanogaster. Studies with exposure to marijuana did not present a profile for our meta-analysis. However, this drug has been less associated with locomotor changes, but alterations in body weight and fat content and changes in cardiac function. Our analyses have shown that fruit flies exposed to drugs of abuse during different developmental stages, such as larvae and adults, exhibit molecular, morphological, behavioral, and survival changes that are dependent on the dosage. These phenotypes resemble the adverse effects of psychoactive substances in clinical medicine.

Karatayev O., Collier A.D., Targoff S.R., Leibowitz S.F.

Clinical studies demonstrate that the risk of developing neurological disorders is increased by overconsumption of the commonly used drugs, alcohol, nicotine and cannabis. These drug-induced neurological disorders, which include substance use disorder (SUD) and its co-occurring emotional conditions such as anxiety and depression, are observed not only in adults but also with drug use during adolescence and after prenatal exposure to these drugs, and they are accompanied by long-lasting disturbances in brain development. This report provides overviews of clinical and preclinical studies, which confirm these adverse effects in adolescents and the offspring prenatally exposed to the drugs and include a more in-depth description of specific neuronal systems, their neurocircuitry and molecular mechanisms, affected by drug exposure and of specific techniques used to determine if these effects in the brain are causally related to the behavioral disturbances. With analysis of further studies, this review then addresses four specific questions that are important for fully understanding the impact that drug use in young individuals can have on future pregnancies and their offspring. Evidence demonstrates that the adverse effects on their brain and behavior can occur: (1) at low doses with short periods of drug exposure during pregnancy; (2) after pre-conception drug use by both females and males; (3) in subsequent generations following the initial drug exposure; and (4) in a sex-dependent manner, with drug use producing a greater risk in females than males of developing SUDs with emotional conditions and female offspring after prenatal drug exposure responding more adversely than male offspring. With the recent rise in drug use by adolescents and pregnant women that has occurred in association with the legalization of cannabis and increased availability of vaping tools, these conclusions from the clinical and preclinical literature are particularly alarming and underscore the urgent need to educate young women and men about the possible harmful effects of early drug use and to seek novel therapeutic strategies that might help to limit drug use in young individuals.

Dahal R., Dharel D., Pokhrel S., Kumar M., Hodgins S., Muhajarine N., Adhikari K., Bhattarai A.

Background: The association of second-hand smoke with prenatal smoking cessation is less studied, and so is the family physician’s role in prenatal smoking cessation. We examined the association between second-hand smoke during pregnancy and having a regular family physician with prenatal smoking cessation in a representative sample of Canadian households. Method: We used the data from Canadian Community Health Surveys (CCHS), 2017–2018, with a sample of 838 women who reported regular (every day) smoking within the 3 months before knowing their last pregnancy. The outcome variable was dichotomized as cessation or continuation of smoking during pregnancy. We used multivariable logistic regression, adjusted for socio-demographic variables, to examine the association of smoking cessation during pregnancy with second-hand smoke and having a regular family physician. Results: Overall, 33.9% (95% confidence interval, 30.0%, 39.2%) of women who were regular smokers before pregnancy reported quitting smoking during pregnancy. The smoking cessation rate was 17.6% (95% CI 11.8, 25.4) among women who had exposure to second-hand smoke and 38.1% (95% CI 32.1, 44.5) women who had a regular family physician. When adjusted for maternal age, maternal education, total household income, and indigenous status, exposure to second-hand smoke was associated with lower odds of smoking cessation during pregnancy, adjusted odds ratios (aOR) of 0.22 (95% CI: 0.12, 0.41) and having a regular family physician was associated with higher odds of quitting smoking [aOR 2.67 (95% CI: 1.23, 5.79)]. Conclusion: Smoking cessation during pregnancy was negatively associated with ongoing exposure to second-hand smoke and was positively associated with having a regular family physician. Contexte: L’association entre l’exposition à la fumée secondaire et le renoncement au tabac pendant la grossesse est moins étudiée, tout comme le rôle du médecin de famille dans le renoncement au tabac pendant la grossesse. Nous avons examiné l’association entre la fumée secondaire pendant la grossesse et le fait d’avoir un médecin de famille régulier et l’abandon du tabagisme prénatal dans un échantillon représentatif de ménages canadiens. Méthode: Nous avons utilisé les données des enquêtes sur la santé dans les collectivités canadiennes (ESCC), 2017–2018, avec un échantillon de 838 femmes qui ont déclaré avoir fumé régulièrement (tous les jours) au cours des trois mois avant de connaitre leur dernière grossesse. La variable de résultat a été divisée en cessation ou poursuite du tabagisme pendant la grossesse. Nous avons utilisé une régression logistique multivariable, ajustée sur les variables sociodémographiques, pour examiner l’association de l’arrêt du tabac pendant la grossesse avec l’exposition à la fumée secondaire et le fait d’avoir un médecin de famille régulier. Résultats: Dans l’ensemble, 33.9% (intervalle de confiance à 95%, 30.0%, 39.2%) des femmes qui fumaient régulièrement avant la grossesse ont déclaré avoir cessé de fumer pendant la grossesse. Le taux d’abandon du tabac était de 17.6% (IC 95% 11.8, 25.4) chez les femmes exposées à la fumée secondaire et de 38.1% (IC 95% 32.1, 44.5) chez les femmes qui avaient un médecin de famille régulier. Après ajustement en fonction de l'âge maternel, du niveau d'éducation de la mère, du revenu total du ménage et du statut d’autochtone, l’exposition à la fumée secondaire était associée à une probabilité plus faible d’arrêt du tabac pendant la grossesse, rapport de cotes ajusté (RCA) de 0.22 (IC à 95%: 0.12, 0.41), et le fait d’avoir un médecin de famille régulier était associé à une probabilité plus élevée d’arrêt du tabac [RCA de 2.67 (IC à 95% : 1.23, 5.79)]. Conclusion: L’arrêt du tabac pendant la grossesse est négativement associé à l’exposition continue à la fumée secondaire et positivement associé au fait d’avoir un médecin de famille régulier.

Khanagar S.B., AlBalawi F., Alshehri A., Awawdeh M., Iyer K., Kumar Bijai L., Aldhebaib A., Gokulchandra Singh O.

Martin R.C., Sandoval I.K., Penner F., Mayes L.C., Potenza M.N., Krishnan-Sarin S., Rutherford H.J.

Ortega L.A., Aragon-Carvajal D.M., Cortes-Corso K.T., Forero-Castillo F.

Considerable progress has been made in elucidating the relationships between early life psychobiological and environmental risk factors and the development of tobacco addiction. However, a comprehensive understanding of the heterogeneity in tobacco addiction phenotypes requires integrating research findings. The probabilistic epigenesis meta-theory offers a valuable framework for this integration, considering systemic, multilevel, developmental, and evolutionary perspectives. In this paper, we critically review relevant research on early developmental risks associated with tobacco addiction and highlight the integrative heuristic value of the probabilistic epigenesis framework for this research. For this, we propose a four-level systems approach as an initial step towards integration, analyzing complex interactions among different levels of influence. Additionally, we explore a coaction approach to examine key interactions between early risk factors. Moreover, we introduce developmental pathways to understand interindividual differences in tobacco addiction risk during development. This integrative approach holds promise for advancing our understanding of tobacco addiction etiology and informing potentially effective intervention strategies.